Practice Essentials

Down syndrome, also called trisomy 21, is a congenital disorder caused by the presence of an extra 21st chromosome. Frequency is about 1 per 800 live births, and each year about 6000 children are born with Down syndrome. Although the clinical presentation of Down syndrome can vary, it is associated with a number of major disorders, including learning disabilities, congential heart defects, duodenal atresia (ie, part of the small intestines is not developed), seizures, childhood leukemia, and early-onset Alzheimer disease. Approximately 50% of children with Down syndrome are born with a heart defect, most often a hole between the sides of the heart. In addition, Hirschsprung disease (congenital aganglionic megacolon), which can cause intestinal obstruction, occurs more frequently in children with Down syndrome than it does in other children.
[1, 2]

The diagnosis of Down syndrome is based on fetal karyotype analyzed predominantly on fetal cells from amniotic fluid sampled by amniocentesis or chronic villus sampling (CVS). Diagnostic tests are invasive and resource-intensive, and because the fetal-placental unit is invaded, these tests pose risks of pain, infection, bleeding, fetal scarring, and fetal loss. Due to the risk of fetal loss inherent to these invasive techniques, they are not offered routinely to all women. Screening consists in targeting patients with an increased risk of chromosomal abnormalities for whom diagnostic testing is then considered.

Screening tests are noninvasive and generally painless studies performed to estimate the risk of a fetus having Down syndrome. These tests do not give a definitive answer as to whether a baby has Down syndrome, but they are used to help parents and clinicians decide whether diagnostic tests are warranted.

Other conditions that should be considered are trisomy 18; trisomy G syndrome; 49,XXXXY chromosome and other high-order multiple X chromosomes; Zellweger syndrome; chromosome 21, mosaic 21 syndrome; and chromosome 21, translocation 21 syndrome. If diagnostic tests yield positive results and parents decide to continue the pregnancy, fetal echocardiography should be performed at 20 weeks' gestation to detect serious cardiac malformations. Ultrasonography should be performed at 28-32 weeks' gestation.

According to the American College of Obstetricians and Gynecologists, all women should be offered screening for aneuploidy before 20 weeks' gestation, and all pregnant women, regardless of their age, should have the option of diagnostic testing.
[1]

Ultrasonography

Ultrasonography is the imaging modality mainstay of prenatal screening and diagnosis of Down syndrome, and it is often used in combination with biochemical tests. Second-trimester ultrasonography helps detect 60-91% cases of Down syndrome, depending on the criteria used. The addition of color Doppler imaging to gray-scale ultrasonography increases the sensitivity for detection of cardiac malformations, which include atrioventricular septal defect (AVSD), abnormalities of the outflow tract, mitral and tricuspid regurgitation, and right-to-left disproportion of the cardiac chamber.
[6, 7, 8, 9, 10, 11, 12]

Ultrasonographic markers include thickness of the nuchal fold, cardiac abnormalities, duodenal atresia, shortened femur, shortened humerus, renal pyelectasis, absence of the nasal bone, a hyperechogenic bowel, and a choroid plexus cyst. An echogenic intracardiac focus has also been identified as a soft marker. None of these markers are specific, and false-positive rates have been reported.

Structural anomalies, cardiac abnormalities, a nuchal fold 6 mm or thicker, bowel echogenicity, choroid plexus cysts, and renal pyelectasis have been studied. With the exception of bowel echogenicity and choroid plexus cysts, the ultrasonographic markers have been found to be more common in fetuses with trisomy 21 than in euploid fetuses. Cardiac anomalies, other structural anomalies, and a nuchal fold 6 mm or thicker were independent predictors of trisomy 21.

Evidence suggests that the careful combination of accurately performed noninvasive ultrasonography and maternal blood testing, eventually followed by a quantitative fluorescent polymerase chain reaction (QF-PCR), should reduce the need for conventional chromosomal analysis, which is relatively time consuming.

A Cochrane Database Review evaluated 22 studies and a total of 32 test combinations formed from 8 different tests and maternal age. The 8 tests included first-trimester nuchal translucency (NT) and the serum markers AFP, uE3, total hCG, free βhCG, inhibin A, PAPP‐A, and ADAM 12. A test strategy involving maternal age and a combination of first-trimester NT and PAPP‐A and second-trimester total hCG, uE3, AFP and Inhibin A outperformed other test combinations.
[6] Another meta-analysis of first-trimester ultrasound screening tests investigated 11 ultrasound markers and 12 serum markers and found that the test strategies that combined ultrasound markers with serum markers (especially PAPP‐A and free βhCG) and maternal age provided better results than those consisting only of ultrasound markers (with or without maternal age), except nasal bone.
[7]

The genetic ultrasonogram scoring index

In a proposed a scoring system for the detection of Down syndrome,
[13] the importance of the clustering of markers forms the basis of the scoring index, such that individual markers are assigned point values based on their sensitivity and specificity in the detection of Down syndrome. The points acquired by each fetus are tabulated into a final score. One study proposed the following scoring system: nuchal fold = 2; major structural defect = 2; and short femur, short humerus, and pyelectasis = 1 each. Selecting fetuses with a score of 2 or more identified 26/32 (81%) Down syndrome fetuses, 9/9 (100%) trisomy-18 fetuses, and 2/2 (100%) trisomy-13 fetuses, but only 26/588 (4.4%) normal fetuses were identified by this scoring system. For a 1/250 risk group, using the ultrasonographic score of 2 resulted in a positive predictive value of 6.87% for Down syndrome and 7.25% for all 3 trisomies.
[14]

Limitations of techniques

First-trimester combined screening at 11 weeks' gestation for Down syndrome is better than second-trimester quadruple screening.
[10, 11] However, at 13 weeks, the results are similar to those of second-trimester quadruple screening. Rates of detecting Down syndrome are high with both stepwise, sequential screening and fully integrated screening, with low rates of false-positive results.

The choice of screening strategy should be between the integrated test, first-trimester combined test, quadruple test, and nuchal translucency measurement, depending on how much service providers are willing to pay, the total budget available, and values on safety. Screening based on maternal age, the second-trimester double test, and the first-trimester serum test is less effective, less safe, and more costly than the integrated test, first-trimester combined test, quadruple test, and nuchal translucency measurement.

One study showed that integrated serum screening was the most cost-effective screening strategy for Down syndrome.
[12] First-trimester combined screening was found to be the most cost-effective strategy if the cost of nuchal translucency was less than $57 or if a genetic ultrasonogram was included in the second-trimester strategies.
[15]

(The image below is that of a fetus with Down syndrome.)

Prenatal ultrasonogram in a fetus at 21 weeks and 1 day of gestation shows shortening of the femur length to 27 mm. This indicates a deficit of 3 weeks in the estimated gestation based on the femoral length.

Nuchal translucency testing

Nuchal translucency (NT) testing is performed between 11 and 14 weeks of pregnancy and involves the use of ultrasonography to measure the clear space in the folds of tissue behind a developing fetus's neck. In fetuses with Down syndrome and other chromosomal abnormalities, fluid tends to accumulate in this location, making the space appear enlarged. Increased nuchal translucency refers to a measurement greater than 3 mm. This finding does not mean that the fetus has a chromosomal abnormality but, rather, indicates that the risks of some genetic disorders and birth defects, including Down syndrome, are increased. This measurement, taken together with the mother's age and the fetus's gestational age, can be used to calculate the odds that the fetus has Down syndrome. With nuchal translucency testing, Down syndrome is correctly detected in about 80% of cases. When performed with a maternal blood test, its accuracy may be improved.
[16, 17, 18]

(See the images below.)

Axial prenatal ultrasonogram of a fetal head demonstrates nuchal thickening and translucency (arrow).

Ultrasonography

Ultrasonography is the mainstay of prenatal screening and diagnosis of Down syndrome, and it is often used in combination with biochemical tests. Second-trimester ultrasonography helps detect 60-91% cases of Down syndrome, depending on the criteria used. The addition of color Doppler imaging to gray-scale ultrasonography increases the sensitivity for detection of cardiac malformations, which include atrioventricular septal defect (AVSD), abnormalities of the outflow tract, mitral and tricuspid regurgitation, and right-to-left disproportion of the cardiac chamber.
[3, 19, 16, 20, 21, 22]

General ultrasonographic markers

The most common sonographic marker is an elevated nuchal translucency (NT). NT testing is performed between 11 and 14 weeks of pregnancy and involves the use of ultrasonography to measure the clear space in the folds of tissue behind a developing baby's neck. In fetuses with Down syndrome and other chromosomal abnormalities, fluid tends to accumulate in this location, making the space appear enlarged. Increased nuchal translucency refers to a measurement greater than 3 mm. This finding does not mean that the fetus has a chromosomal abnormality but, rather, indicates that the risks of some genetic disorders and birth defects, including Down syndrome, are increased. This measurement, taken together with the mother's age and the fetus's gestational age, can be used to calculate the odds that the baby has Down syndrome. With nuchal translucency testing, Down syndrome is correctly detected in about 80% of cases. When performed with a maternal blood test, its accuracy may be improved.
[16, 17]

(See the images below.)

Axial prenatal ultrasonogram of a fetal head demonstrates nuchal thickening and translucency (arrow).

Second-trimester ultrasound findings, termed "soft markers" because they may be transient, may nclude cardiac abnormalities, duodenal atresia, absent nasal bone, shortened femur, shortened humerus, pyelectasis or hydronephrosis, echogenic bowel, cardiac echogenic chorda tendineae (“golf ball”), and choroid plexus cysts (CPC, which is related more to trisomy 18).
[23] An echogenic intracardiac focus (EIF) has also been identified as a second-trimester soft marker.
[24] None of these markers are specific, and false-positive rates have been reported.

The absence of a nasal bone is a powerful marker for Down syndrome. A short nasal bone is associated with an increased likelihood of fetal Down syndrome in a high-risk population. The ratio of prenasal thickness to nasal bone length (PT/NBL) has been found to be a valuable first-trimester screening marker for Down syndrome.
[21, 22, 25]

(See the images below.)

Prenatal ultrasonogram in a fetus at 21 weeks and 1 day of gestation shows shortening of the femur length to 27 mm. This indicates a deficit of 3 weeks in the estimated gestation based on the femoral length.

Pelvic and cerebral diameters

Although the diameters of the pelvis and the cerebrum are individually statistically significant as markers of trisomy 21, the combination of transcerebellar diameter (TCD) and frontothalamic distance (FTD) measurements may be superior to the measurement of either parameter alone.

Patients with Down syndrome have a large mean iliac angle and a shortened mean iliac length. The most pronounced differences are at the middle sacral level. This observation suggests that the middle sacral level may be the optimal level for measuring the iliac angle and length during prenatal ultrasonography.
[22]

The iliac angle is significantly greater in second-trimester fetuses with trisomy 21 than in euploid fetuses. The iliac angle varies with the axial level, with the widest angle being at the most superior level. Evidence supports the measurement of the iliac angle at the most superior level as a potential marker for Down syndrome on prenatal ultrasonography.

Measurements of the axial iliac angle on standardized 3-dimensional multiplanar views of the pelvis are reliable and can be used to identify some fetuses at increased risk for trisomy 21.

In the second trimester, the nasal bones are present in most fetuses with trisomy 21. These fetuses have a characteristic midfacial anthropometry.

Best ultrasonographic markers to detect trisomy 21 in the second trimester

Structural anomalies, cardiac abnormalities, a nuchal fold 6 mm or thicker, bowel echogenicity, choroid plexus cysts (see the first image below), and renal pyelectasis (see the second and third images below) have been studied. With the exception of bowel echogenicity and choroid plexus cysts, the ultrasonographic markers have been found to be more common in fetuses with trisomy 21 than in euploid fetuses. Cardiac anomalies, other structural anomalies, and a nuchal fold 6 mm or thicker were the only independent predictors of trisomy 21. When any of the ultrasonographic markers significant in univariate analysis are considered, the false-positive rate is reported to be 5.3%, and the sensitivity is reported to be 59.1%. When any of the predictors from multivariate analysis are present, the false-positive rate has been reported as 3.1%, and the sensitivity 54.5%. Because of the considerable overlap of ultrasonographic markers in fetuses with trisomy 21, use of markers that are not independent predictors increases the false-positive rate without a gain in sensitivity.
[8, 9, 11, 12, 16, 20, 23, 24]

Axial prenatal ultrasonogram of the abdomen obtained at the level of the kidneys demonstrates bilateral renal pyelectasis (arrows).

Prenatal ultrasonogram in a fetus at 21 weeks and 1 day of gestation shows shortening of the femur length to 27 mm. This indicates a deficit of 3 weeks in the estimated gestation based on the femoral length.

Axial prenatal ultrasonogram of a fetal head demonstrates nuchal thickening and translucency (arrow).

Longitudinal prenatal ultrasonogram shows nuchal thickening (arrow).

Axial prenatal ultrasonogram of the head shows a choroid plexus cyst (arrow) in the lateral ventricle.

Axial prenatal ultrasonogram of the abdomen obtained at the level of the kidneys demonstrates bilateral renal pyelectasis (arrows).

The authors extend their sincere thanks to Mrs Helen Lee, ultrasonographer, Liverpool Women's NHS Trust and Royal Liverpool Children's NHS Trust, for her help in compiling prenatal sonograms for this article.